tbuckley/cabot-search huggingface dataset:
Concomitant Use of Proton Pump Inhibitors and Palbociclib Among Patients With Breast Cancer
Authors: Ju-Eun Lee, Sun-Hong Kwon, Swan Kwon, Hye-In Jung, Jin Hyun Nam, Eui-Kyung Lee
Journal: JAMA Network Open (2023)

Proton pump inhibitors (PPIs) are commonly used drugs to relieve gastrointestinal tract symptoms, but their acid-inhibitory action negatively affects the bioavailability and clinical outcomes of orally administered concomitant drugs.To identify the clinical outcomes of patients with advanced breast cancer who concomitantly use PPIs and palbociclib.This retrospective cohort study used nationwide claims data between November 1, 2016, and July 31, 2021, in South Korea. Patients with breast cancer receiving palbociclib between November 1, 2017, and July 31, 2020, were identified. Patients whose prescriptions for palbociclib and PPI overlapped by at least 33% were classified into a concomitant PPI group. Patients who never received PPI during the palbociclib treatment period were classified into a nonconcomitant PPI group. Patients were selected through 1:3 propensity score matching for analyses.Concomitant use of PPIs with palbociclib.Time to progression and death. These outcomes were presented as progression-free survival (PFS) and overall survival (OS) and were analyzed using the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was used to estimate the hazard ratio (HR) of concomitant PPI use associated with clinical PFS and/or OS.A total of 344 women were included in the concomitant PPI group and 966 in the nonconcomitant PPI group. Among 1310 patients identified after matching, 1108 (84.6%) were older than 50 years; 1111 (84.8%) were treated with letrozole and anastrozole (endocrine sensitive); and 199 (15.2%) were treated with fulvestrant (endocrine resistant). The median clinical PFS in the concomitant PPI group was shorter than that of the nonconcomitant PPI group (25.3 [95% CI, 19.6-33.0] vs 39.8 [95% CI, 34.9 to not applicable] months; P < .001), and the HR was 1.76 (95% CI, 1.46-2.13). Concomitant use of PPI was also associated with shorter OS (HR, 2.71 [95% CI, 2.07-3.53]). Both clinical PFS and OS in the concomitant PPI group were consistently poor in patients receiving endocrine-sensitive and endocrine-resistant treatment.These findings suggest that concomitant use of PPIs with palbociclib may hinder the complete therapeutic benefits of palbociclib in patients with breast cancer.
The global economic burden of chronic obstructive pulmonary disease for 204 countries and territories in 2020–50: a health-augmented macroeconomic modelling study
Authors: Simiao Chen, Michael Kuhn, Klaus Prettner, Fengyun Yu, Ting Yang, Till Bärnighausen, David E Bloom, Chen Wang
Journal: The Lancet Global Health (2023)

BackgroundChronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and imposes a substantial economic burden. Gaining a thorough understanding of the economic implications of COPD is an important prerequisite for sound, evidence-based policy making. We aimed to estimate the macroeconomic burden of COPD for each country and establish its distribution across world regions.MethodsIn this health-augmented macroeconomic modelling study we estimated the macroeconomic burden of COPD for 204 countries and territories over the period 2020–50. The model accounted for (1) the effect of COPD mortality and morbidity on labour supply, (2) age and sex specific differences in education and work experience among those affected by COPD, and (3) the impact of COPD treatment costs on physical capital accumulation. We obtained data from various public sources including the Global Burden of Disease Study 2019, the World Bank database, and the literature. The macroeconomic burden of COPD was assessed by comparing gross domestic product (GDP) between a scenario projecting disease prevalence based on current estimates and a counterfactual scenario with zero COPD prevalence from 2020 to 2050.FindingsOur findings suggest that COPD will cost the world economy INT$4·326 trillion (uncertainty interval 3·327–5·516; at constant 2017 prices) in 2020–50. This economic effect is equivalent to a yearly tax of 0·111% (0·085–0·141) on global GDP. China and the USA face the largest economic burdens from COPD, accounting for INT$1·363 trillion (uncertainty interval 1·034–1·801) and INT$1·037 trillion (0·868–1·175), respectively.InterpretationThe macroeconomic burden of COPD is large and unequally distributed across countries, world regions, and income levels. Our study stresses the urgent need to invest in global efforts to curb the health and economic burdens of COPD. Investments in effective interventions against COPD do not represent a burden but could instead provide substantial economic returns in the foreseeable future.FundingAlexander von Humboldt Foundation, National Natural Science Foundation of China, CAMS Innovation Fund for Medical Science, Chinese Academy of Engineering project, Chinese Academy of Medical Sciences and Peking Union Medical College project, and Horizon Europe.TranslationsFor the Chinese and German translations of the abstract see Supplementary Materials section.
γδ T cell dichotomy with opposing cytotoxic and wound healing functions in human solid tumors
Authors: Cathal Harmon, Alexandra Zaborowski, Haim Moore, Pamela St. Louis, Karen Slattery, Danielle Duquette, John Scanlan, Harry Kane, Britta Kunkemoeller, Claire L. McIntyre, Aine Ni Scannail, Bruce Moran, Ana C. Anderson, Des Winter, Donal Brennan, Michael A. Brehm, Lydia Lynch
Journal: Nature Cancer (2023)
Shared and Distinct Gut Microbiota in Spondyloarthritis, Acute Anterior Uveitis, and Crohn's Disease
Authors: Morgan Essex, Valeria Rios Rodriguez, Judith Rademacher, Fabian Proft, Ulrike Löber, Lajos Markó, Uwe Pleyer, Till Strowig, Jérémy Marchand, Jennifer A. Kirwan, Britta Siegmund, Sofia K. Forslund, Denis Poddubnyy
Journal: Arthritis & Rheumatology (2023)

Spondyloarthritis (SpA) is a group of immune-mediated diseases highly concomitant with nonmusculoskeletal inflammatory disorders, such as acute anterior uveitis (AAU) and Crohn's disease (CD). The gut microbiome represents a promising avenue to elucidate shared and distinct underlying pathophysiology.
EGFR/IGF1R Signaling Modulates Relaxation in Hypertrophic Cardiomyopathy
Authors: Sila Algül, Maike Schuldt, Emmy Manders, Valentijn Jansen, Saskia Schlossarek, Richard de Goeij-de Haas, Alex A. Henneman, Sander R. Piersma, Connie R. Jimenez, Michelle Michels, Lucie Carrier, Michiel Helmes, Jolanda van der Velden, Diederik W.D. Kuster
Journal: Circulation Research (2023)

Diastolic dysfunction is central to diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy (HCM). However, therapies that improve cardiac relaxation are scarce, partly due to a limited understanding of modulators of cardiomyocyte relaxation. We hypothesized that cardiac relaxation is regulated by multiple unidentified proteins and that dysregulation of kinases contributes to impaired relaxation in patients with HCM.We optimized and increased the throughput of unloaded shortening measurements and screened a kinase inhibitor library in isolated adult cardiomyocytes from wild-type mice. One hundred fifty-seven kinase inhibitors were screened. To assess which kinases are dysregulated in patients with HCM and could contribute to impaired relaxation, we performed a tyrosine and global phosphoproteomics screen and integrative inferred kinase activity analysis using HCM patient myocardium. Identified hits from these 2 data sets were validated in cardiomyocytes from a homozygous MYBPC3c.2373insG HCM mouse model.Screening of 157 kinase inhibitors in wild-type (N=33) cardiomyocytes (n=24 563) resulted in the identification of 17 positive inotropes and 21 positive lusitropes, almost all of them novel. The positive lusitropes formed 3 clusters: cell cycle, EGFR (epidermal growth factor receptor)/IGF1R (insulin-like growth factor 1 receptor), and a small Akt (α-serine/threonine protein kinase) signaling cluster. By performing phosphoproteomic profiling of HCM patient myocardium (N=24 HCM and N=8 donors), we demonstrated increased activation of 6 of 8 proteins from the EGFR/IGFR1 cluster in HCM. We validated compounds from this cluster in mouse HCM (N=12) cardiomyocytes (n=2023). Three compounds from this cluster were able to improve relaxation in HCM cardiomyocytes.We showed the feasibility of screening for functional modulators of cardiomyocyte relaxation and contraction, parameters that we observed to be modulated by kinases involved in EGFR/IGF1R, Akt, cell cycle signaling, and FoxO (forkhead box class O) signaling, respectively. Integrating the screening data with phosphoproteomics analysis in HCM patient tissue indicated that inhibition of EGFR/IGF1R signaling is a promising target for treating impaired relaxation in HCM.
Error in Conflict of Interest Disclosures
Journal: JAMA (2023)

Leonard H. Epstein, PhD; Denise E. Wilfley, PhD; Colleen Kilanowski, MS; Teresa Quattrin, MD; Steven R. Cook, MD, MPH; Ihuoma U. Eneli, MD; Nancy Geller, PhD; Daphne Lew, PhD; Michael Wallendorf, PhD; Peter Dore, MA; Rocco A. Paluch, MA; Kenneth B. Schechtman, PhD
Sodium–glucose cotransporter‐2 inhibitors in heart failure: Potential decongestive mechanisms and current clinical studies
Authors: Jan Biegus, Marat Fudim, Husam M. Salah, Hiddo J.L. Heerspink, Adriaan A. Voors, Piotr Ponikowski
Journal: European Journal of Heart Failure (2023)

Congestion is a key pathophysiological feature of heart failure (HF) syndrome that drives most of the clinical manifestations of acute HF and is related with poor quality of life and outcomes. Therefore, safe and effective decongestion is an important therapeutic target in the management of acute HF and despite the use of guideline-recommended loop diuretics, adequate decongestion is not always achieved in patients with acute HF. Recently, sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to provide clinical benefits across a broad spectrum of patients with HF, including consistent reduction in the risk of acute HF episodes. While the exact mechanisms underlying these benefits remain a matter of debate, a growing body of evidence suggests that effective decongestion may be partly responsible, especially in the setting of acute HF. In this review, we discuss the potential decongestive mechanisms of SGLT-2 inhibitors, such as osmotic diuresis, natriuresis, preservation of glomerular filtration and facilitation of interstitial drainage, which can collectively translate into effective and safe decongestion. Furthermore, we provide a comprehensive review of up-to-date clinical data of SGLT-2 inhibitor use in the acute HF population.
Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future
Authors: Sarah A. Holstein, Shakira J. Grant, Tanya M. Wildes
Journal: Journal of Clinical Oncology (2023)

Historically, the outcomes for individuals with triple-class refractory and penta-drug refractory multiple myeloma (MM) have been poor because of a dearth of effective treatment options. However, the advent of chimeric antigen receptor (CAR) T-cell and T-cell redirecting bispecific antibody (BsAb) therapies has led to unprecedented response rates and durations of response in heavily relapsed/refractory (R/R) populations. Currently, two B-cell maturation antigen (BCMA)-directed CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) as well as one BCMA/CD3 BsAb (teclistamab) have been approved for late-line (greater than four previous lines) R/R MM in the United States. The purpose of this review is to analyze the recent data for these approved therapies as well as provide an overview of other related CAR T-cell and BsAb therapies under development, including non-BCMA-targeting agents. We review efficacy and safety considerations, with particular focus on cytokine release syndrome, neurotoxicity, and infection risk. The relative merits and limitations of each class of therapy are discussed, as well as the areas of unmet need with respect to optimal sequencing and supportive care measures. We examine the factors that challenge equitable access to these novel therapies across minoritized racial, ethnic, and socioeconomic populations. Although it is evident that CAR T-cell and BsAb therapies will transform treatment paradigms in MM for years to come, significant work remains to identify the optimal utilization of these novel therapies and ensure equitable access.
Genotyping and population characteristics of the China Kadoorie Biobank
Authors: Robin G. Walters, Iona Y. Millwood, Kuang Lin, Dan Schmidt Valle, Pandora McDonnell, Alex Hacker, Daniel Avery, Ahmed Edris, Hannah Fry, Na Cai, Warren W. Kretzschmar, M. Azim Ansari, Paul A. Lyons, Rory Collins, Peter Donnelly, Michael Hill, Richard Peto, Hongbing Shen, Xin Jin, Chao Nie, Xun Xu, Yu Guo, Canqing Yu, Jun Lv, Robert J. Clarke, Liming Li, Zhengming Chen
Journal: Cell Genomics (2023)

The China Kadoorie Biobank (CKB) is a population-based prospective cohort of >512,000 adults recruited from 2004 to 2008 from 10 geographically diverse regions across China. Detailed data from questionnaires and physical measurements were collected at baseline, with additional measurements at three resurveys involving ∼5% of surviving participants. Analyses of genome-wide genotyping, for >100,000 participants using custom-designed Axiom arrays, reveal extensive relatedness, recent consanguinity, and signatures reflecting large-scale population movements from recent Chinese history. Systematic genome-wide association studies of incident disease, captured through electronic linkage to death and disease registries and to the national health insurance system, replicate established disease loci and identify 14 novel disease associations. Together with studies of candidate drug targets and disease risk factors and contributions to international genetics consortia, these demonstrate the breadth, depth, and quality of the CKB data. Ongoing high-throughput omics assays of collected biosamples and planned whole-genome sequencing will further enhance the scientific value of this biobank.
Safety and Efficacy of Anlotinib Hydrochloride Plus Temozolomide in Patients with Recurrent Glioblastoma
Authors: Qingsheng Xu, Kaiyuan Huang, Xiangqi Meng, Yuxiang Weng, Luyuan Zhang, Linghao Bu, Xiujue Zheng, Jinquan Cai, Renya Zhan, Qun Chen
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Glioblastoma (GBM) is a highly vascularized tumor with few treatment options after disease recurrence. Here, we report the efficacy and safety of anlotinib hydrochloride plus temozolomide in patients with recurrent GBM. Patients and Methods: Patients with first definite postsurgical progression of histologically confirmed GBM preceded by standard radiotherapy and temozolomide chemotherapy were eligible for inclusion. All patients received temozolomide (150–200 mg/m2, orally, every day (QD) d1–5/4 wk) and anlotinib (10 mg, orally, QD, d1–14/3 wk) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by the Response Assessment in Neuro-Oncology (RANO) criteria. Results: Twenty-one patients were enrolled between May 2020 and July 2021, with a median age of 55 (range 27–68) years old. According to the Response Assessment in Neuro-Oncology (RANO) criteria, tumor response occurred in 17 patients, of which 9 patients had a complete response, and the objective response rate was 81.0% [95% confidence interval (CI), 62.6–99.3]. The disease control rate was 95.2% (95% CI, 76.2–99.9), with three additional patients achieving a stable disease without tumor progression. The median PFS was 7.3 months (95% CI, 4.9–9.7), and the 6-month PFS rate was 61.9% (95% CI, 39.3–84.6). The median overall survival was 16.9 months (95% CI, 7.8–26.0). The most common adverse events were leukocytopenia (66.7%), thrombocytopenia (38.1%), and hypertriglyceridemia (38.1%). Five patients had nine grade 3 adverse events, with a 23.8% incidence rate. Two patients discontinued therapy due to ischemic stroke (grade 3) and wound dehiscence (grade 1), respectively. No grade 4 or treatment-related deaths occurred in this study. Conclusions: Anlotinib combined with temozolomide is efficacious and tolerated in patients with recurrent GBM.
Axonal energy metabolism, and the effects in aging and neurodegenerative diseases
Authors: Sen Yang, Jung Hyun Park, Hui-Chen Lu
Journal: Molecular Neurodegeneration (2023)

Abstract Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of aging (NDAs), such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic lateral sclerosis. Glucose is the major brain fuel and glucose hypometabolism has been observed in brain regions vulnerable to aging and NDAs. Many neurodegenerative susceptible regions are in the topological central hub of the brain connectome, linked by densely interconnected long-range axons. Axons, key components of the connectome, have high metabolic needs to support neurotransmission and other essential activities. Long-range axons are particularly vulnerable to injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy is often an early sign of neurodegeneration. Recent studies ascribe axonal maintenance failures to local bioenergetic dysregulation. With this review, we aim to stimulate research in exploring metabolically oriented neuroprotection strategies to enhance or normalize bioenergetics in NDA models. Here we start by summarizing evidence from human patients and animal models to reveal the correlation between glucose hypometabolism and connectomic disintegration upon aging/NDAs. To encourage mechanistic investigations on how axonal bioenergetic dysregulation occurs during aging/NDAs, we first review the current literature on axonal bioenergetics in distinct axonal subdomains: axon initial segments, myelinated axonal segments, and axonal arbors harboring pre-synaptic boutons. In each subdomain, we focus on the organization, activity-dependent regulation of the bioenergetic system, and external glial support. Second, we review the mechanisms regulating axonal nicotinamide adenine dinucleotide (NAD + ) homeostasis, an essential molecule for energy metabolism processes, including NAD + biosynthetic, recycling, and consuming pathways. Third, we highlight the innate metabolic vulnerability of the brain connectome and discuss its perturbation during aging and NDAs. As axonal bioenergetic deficits are developing into NDAs, especially in asymptomatic phase, they are likely exaggerated further by impaired NAD + homeostasis, the high energetic cost of neural network hyperactivity, and glial pathology. Future research in interrogating the causal relationship between metabolic vulnerability, axonopathy, amyloid/tau pathology, and cognitive decline will provide fundamental knowledge for developing therapeutic interventions.
What is an isocitrate dehydrogenase-mutated central nervous system World Health Organization grade 2 glioma, or who should receive vorasidenib?
Authors: Matthias Preusser, Marjolein Geurts, Johannes A Hainfellner, Martin J van den Bent
Journal: Neuro-Oncology (2023)

Journal Article What is an isocitrate dehydrogenase-mutated central nervous system World Health Organization grade 2 glioma, or who should receive vorasidenib? Get access Matthias Preusser, Matthias Preusser Division of Oncology, Department of Medicine 1, Medical University, Vienna, Austria Corresponding Author: Matthias Preusser, MD, Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria (matthias.preusser@meduniwien.ac.at). https://orcid.org/0000-0003-3541-2315 Search for other works by this author on: Oxford Academic PubMed Google Scholar Marjolein Geurts, Marjolein Geurts The Brain Tumour Center at the Erasmus MC Cancer Institute, Rotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Johannes A Hainfellner, Johannes A Hainfellner Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria Search for other works by this author on: Oxford Academic PubMed Google Scholar Martin J van den Bent Martin J van den Bent The Brain Tumour Center at the Erasmus MC Cancer Institute, Rotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 11, November 2023, Pages 1915–1917, https://doi.org/10.1093/neuonc/noad113 Published: 21 July 2023 Article history Corrected and typeset: 21 July 2023 Published: 21 July 2023
Placental drug transport and fetal exposure during pregnancy is determined by drug molecular size, chemistry, and conformation
Authors: Katherine C. Fein, Mariah L. Arral, Julie S. Kim, Alexandra N. Newby, Kathryn A. Whitehead
Journal: Journal of Controlled Release (2023)

Pregnant people are unable to take many prescription and over-the-counter medications because of suspected or known risk to the fetus. This undermedication contributes to the high maternal mortality rate in the United States and detracts from the quality of life of pregnant people. As such, there is an urgent need to develop safe pharmaceutical formulations for use during pregnancy. Most drugs are small molecules that easily cross the placenta, which is the biological barrier that separates the maternal and fetal bloodstreams. One potential approach to preventing fetal drug accumulation is to design drug compounds that are excluded by the placenta; however, there is little understanding of how macromolecular drug properties affect transplacental transport. To address this knowledge gap, we examined the transport behavior of fluorescently-labeled polymers with varying size, conformation, and chemistry. We compared these polymers to unconjugated fluorescein, a small molecule model drug that readily crosses biological barriers. We found that molecular size affected transplacental transport in an in vitro model, BeWo b30 monolayers, as well as in pregnant mice, with larger polymers having lower permeability. In addition to size, polymer chemistry altered behavior, with polyethylene glycol (PEG) molecules permeating the placental barrier to a greater extent than dextrans of equivalent molecular weight. PEG molecules were also more readily taken up into placental cells in vivo. These findings will inform the future development of drug conjugates or other macromolecular medicines that can safely be used during pregnancy.
Submillimeter Multifunctional Ferromagnetic Fiber Robots for Navigation, Sensing, and Modulation
Authors: Yujing Zhang, Xiaobo Wu, Ram Anand Vadlamani, Youngmin Lim, Jongwoon Kim, Kailee David, Earl Gilbert, You Li, Ruixuan Wang, Shan Jiang, Anbo Wang, Harald Sontheimer, Daniel Fine English, Satoru Emori, Rafael V. Davalos, Steven Poelzing, Xiaoting Jia
Journal: Advanced Healthcare Materials (2023)

Small-scale robots capable of remote active steering and navigation offer great potential for biomedical applications. However, the current design and manufacturing procedure impede their miniaturization and integration of various diagnostic and therapeutic functionalities. Herein, submillimeter fiber robots that can integrate navigation, sensing, and modulation functions are presented. These fiber robots are fabricated through a scalable thermal drawing process at a speed of 4 meters per minute, which enables the integration of ferromagnetic, electrical, optical, and microfluidic composite with an overall diameter of as small as 250 µm and a length of as long as 150 m. The fiber tip deflection angle can reach up to 54